All publications cited herein are incorporated by reference in their entirety to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. The following description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
WHO grade IV astrocytoma or glioblastoma (GBM) are the most common primary brain tumors and, unfortunately, the most aggressive. Median survival of patients harboring these tumors is approximately 14 months. Despite a committed effort to investigate new chemotherapies, molecularly targeted therapies, immunotherapies, surgical and radiological approaches, there has been little improvement over the last 30 years. Inadequate classification of GBM may have contributed to the difficulty of developing new therapies by decreasing power of clinical trials and underestimating benefit of class-specific drugs. It may also have confounded discovery of class-specific pathways and drug targets.
GBM diagnosed by histopathology is a collection of molecular and clinical subtypes. For example, there are two classes of GBM based on clinical presentation [1], [2]. Primary GBM arise de novo in older patients and are associated with poorer prognosis. Secondary GBM are rare (˜5-10% of total GBM), progress from lower grade tumors, occur more frequently in younger patients with better prognosis and have a different molecular profile. Studies using gene expression, DNA copy number, miRNA, and DNA methylation show these molecular characteristics can divide GBM into subclasses, some with different clinical characteristics [3], [4], [5], [6], [7], [8], [9]. Three subtypes emerged in early studies of WHO grade IV GBM (studies that combine histological subtypes or grades of glioma and use molecular classification to distinguish them are excluded from this discussion). These were called proneural (PN), Proliferative (PROLIF) and mesenchymal (MES) and each had characteristic clinical and molecular features [4]. Later approaches find 3-5 GBM subtypes including the PN, MES and Classical (CLAS) subgroups [8], [9], [10], [11]. DNA methylation identifies a subset of PN tumors with glioma CpG island methylator phenotype (GCIMP) that are younger, longer surviving and tightly associated with IDH1 mutations [8].
However, molecular classification of GBM is still in its infancy. There is no consensus on the number of subtypes and which classifiers should be used to classify them. In addition, there is considerable reassignment of tumors to different classes depending on classifier used. There is also little information on which oncogenic pathways are active in subtypes and how subtypes respond to standard and experimental therapeutics.
Alterations in the growth factor receptor/phosphatidylinositol 3-kinase/AKT (GFR/PI3K/AKT) pathway occur in most human cancers including at least 85% of GBM [10]. Pharmacological inhibition of the GFR/PI3K/AKT pathway is a promising strategy for anti-cancer therapy [12], [13]. However, while sporadic responses have been reported, clinical trials of pathway inhibitors in GBM have been largely disappointing [14].